Path: /proteins/c9orf72-dpr-protein
Title: C9orf72 DPR Protein
Tags: section:proteins, kind:protein
| C9orf72 DPR Protein |
|---|
| Gene | [C9orf72](/entities/c9orf72) |
| UniProt ID | [Q9NS67](https://www.uniprot.org/uniprot/Q9NS67) |
| PDB Structures | None available |
| Molecular Weight | Dipeptide repeats: 5-20 kDa |
| Subcellular Localization | Cytoplasm, Nucleus |
The C9orf72 dipeptide repeat (DPR) proteins are toxic polyl glycine-proline (poly-GP) and poly-proline-alanine (poly-PA) species generated by unconventional translation of the hexanucleotide repeat expansion in the C9orf72 gene. This repeat expansion is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
- The GGGGCC hexanucleotide repeat expansion in the first intron of C9orf72
- Normal: < 30 repeats
- Pathogenic: hundreds to thousands of repeats
- Leads to three pathogenic mechanisms:
The repeat expansion undergoes:
- RNA foci formation - toxic RNA species sequester RNA-binding proteins
- RAN translation - translation in all reading frames produces DPRs
- Loss of function - reduced C9orf72 protein expression
Five different dipeptide repeats are produced:
| Dipeptide |
Reading Frame |
Toxicity |
| Poly-GA |
+1 frame |
High |
| Poly-GP |
+2 frame |
Moderate |
| Poly-GR |
+1 frame (antisense) |
High |
| Poly-PR |
+2 frame (antisense) |
High |
| Poly-PA |
+3 frame |
Low |
- RNA foci sequester essential RNA-binding proteins
- Disrupts RNA splicing and trafficking
- Affects nucleocytoplasmic transport
- Poly-GA: Forms inclusions, disrupts proteostasis
- Poly-GR/PR: Interferes with nucleocytoplasmic transport
- Nucleolar stress: DPRs accumulate in nucleolus
- Stress granule formation: Alters stress response
- Autophagy-lysosome pathway dysfunction
- Impaired trafficking of cellular proteins
- Altered immune response
- C9orf72 is the most common genetic cause of ALS
- Motor neuron degeneration through toxic DPRs
- RNA foci found in motor neurons of patients
- TDP-43 pathology co-occurs with DPR inclusions
- Frontotemporal lobar degeneration with motor neuron disease
- Behavioral variant FTD is common presentation
- Both ALS and FTD can occur in the same patient
- Mixed pathology common in C9orf72 carriers
- DPRs found alongside TDP-43 and tau pathology
- Antisense oligonucleotides (ASOs) to reduce repeat-containing RNA
- Small molecules to bind repeat RNA
- RNA foci dispersants
- Autophagy enhancers to clear DPR inclusions
- Small molecules to inhibit RAN translation
- Antibodies against specific DPR species
- CRISPR-based approaches to reduce repeat expansion
- Allele-specific silencing
- Increasing endogenous C9orf72 expression
- Poly-GP in cerebrospinal fluid (CSF)
- Neurofilament light chain (NfL) in blood
- Tau and amyloid markers
- Frontal and temporal lobe atrophy on MRI
- Hypometabolism on FDG-PET
- White matter abnormalities on DTI